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Vertex Pharmaceuticals Incorporated Message Board

  • thirdmeinvestor thirdmeinvestor Oct 1, 2013 12:04 AM Flag

    An interesting article printed in NEJM

    Ivacaftor in a G551D Homozygote with Cystic Fibrosis

    To the Editor:
    Recent studies provide support for the usefulness of the oral potentiator ivacaftor in patients with cystic fibrosis who are heterozygous for the G551D mutation. The possibility of an increased response in persons who are homozygous for the mutation is unknown because of its low prevalence. Ivacaftor potentiates the open-channel probability of the G551D–cystic fibrosis transmembrane conductance regulator (CFTR) protein.1 The most common cystic fibrosis mutation, F508del, results in little or no CFTR reaching the cell surface, whereas with the G551D-CFTR mutation, there are potentially normal levels of nonfunctional CFTR channels at the cell surface.2Therefore, we postulate the increased efficacy of ivacaftor in G551D homozygotes as compared with compound heterozygotes with a single G551D mutation. Furthermore, little is known about the response to ivacaftor in persons with a forced expiratory volume in 1 second (FEV1) of less than 30% of the predicted value, because these persons were excluded from initial studies.1,3
    We report the use of ivacaftor in a 19-year-old woman who was homozygous for the G551D mutation. After a period of progressive deterioration with recurrent infective exacerbations (seven separate courses of intravenous antibiotics in the previous 12 months), the baseline FEV1 had decreased to 24% of the predicted value, she had become dependent on oxygen, and she was referred for assessment for lung transplantation. Simultaneously, ivacaftor therapy was initiated. Within 8 weeks, the FEV1 had increased to 35% of the predicted value, continuous oxygen was discontinued with a resting oxygen saturation of 95% (it was previously 85%) while the patient was breathing ambient air, and assessment for transplantation was deferred. Prospectively, over the subsequent 12 months of therapy, she required one course of intravenous antibiotics, the FEV1increased by 16 percentage points (from 24 to 40% of the predicted value), the sweat chloride level decreased from 92 mmol per liter to 18 mmol per liter, the 6-minute walk distance increased by 410 m (from 140 to 550 m), and the weight increased by 8.4 kg (from 42.0 to 50.4 kg)

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    • The albumin level being a surrogate for improved nutritional status via improved gi function/absorption.

    • The progression of improvements in all indicators continued without plateauing through 52 weeks where the dosing stopped. The absolute changes in % FEV1 were 9%, 13%, 15%, 16%, at Week 10, Week 20, Week 30, and at Week 52, respectively. If you extrapolate the trend, it will continue to rise beyond Week 52. Her weight gain was also impressive; she gained 18.5 lbs (=8.4kg, from 42kg(= 92.6 lbs.) to 50.4kg(=111.1 lbs.)) for the treatment duration of 52 weeks. It is too bad that this Yahoo board does not allow transfer of the charts.

      One probable corollary to these results is that when VX-661 and Kalydeco were dosed for 508/551 heterozygotes, an analogous progression of continuous improvements in all indicators would be observed. Another possible corollary is that 809+Kalydeco might improve indicators beyond 12 weeks for 508 homozygote.

    • Good find 3rd, and more corroborating potential!

    • In addition, the serum albumin level increased from 3.3 g per deciliter to 4.5 g per deciliter, and the daily consumption of pancreatic-enzyme supplements decreased by approximately 60%.
      In the VX08-770-105 clinical-trial cohort of patients who were heterozygous for the G551D mutation,1 the improvements in sweat chloride levels and the FEV1 reached a plateau after 2 weeks. To date, we have not found a plateau effect with ivacaftor therapy in our G551D homozygous patient. The progressive reduction and normalization of the sweat chloride level (a marker of CFTR dysfunction), coupled with the continued clinical improvements in lung function, weight, and walk distance throughout the 12-month follow-up period provide support for the increased efficacy of ivacaftor in homozygous versus heterozygous patients. Ireland has the highest reported frequency of the G551D mutation worldwide, at 12% (as compared with 4.4% in the United States), and eight persons with cystic fibrosis in Ireland are known to be homozygous for the G551D mutation.4,5 Prospective analysis involving this cohort may confirm our observation.

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